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A novel allosteric inhibitor of the uridine diphosphate n-acetylglucosamine pyrophosphorylase from Trypanosoma brucei

DOI: 10.1021/cb400411x DOI Help
PMID: 23834437 PMID Help

Authors: Michael D. Urbaniak (University of Dundee) , Iain T. Collie (University of Dundee) , Wenxia Fang (University of Dundee) , Tonia Aristotelous (University of Dundee) , Susanne Eskilsson (University of Dundee) , Olawale G. Raimi (University of Dundee) , Justin Harrison (University of Dundee) , Iva Hopkins Navratilova (University of Dundee) , Julie A. Frearson (University of Dundee) , Daan M. F. Van Aalten (University of Dundee) , Michael A. J. Ferguson (University of Dundee)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acs Chemical Biology , VOL 8 (9) , PAGES 1981 - 1987

State: Published (Approved)
Published: September 2013

Open Access Open Access

Abstract: Bacteriocin; P aeruginosa.; pyocin S2; pyocin AP41; immunity protein Uridine diphosphate N-acetylglucosamine pyrophosphorylase (UAP) catalyzes the final reaction in the biosynthesis of UDP-GlcNAc, an essential metabolite in many organisms including Trypanosoma brucei, the etiological agent of Human African Trypanosomiasis. High-throughput screening of recombinant T. brucei UAP identified a UTP-competitive inhibitor with selectivity over the human counterpart despite the high level of conservation of active site residues. Biophysical characterization of the UAP enzyme kinetics revealed that the human and trypanosome enzymes both display a strictly ordered bi−bi mechanism, but with the order of substrate binding reversed. Structural characterization of the T. brucei UAP−inhibitor complex revealed that the inhibitor binds at an allosteric site absent in the human homologue that prevents the conformational rearrangement required to bind UTP. The identification of a selective inhibitory allosteric binding site in the parasite enzyme has therapeutic potential.

Journal Keywords: Catalytic; Humans; Nucleotidyltransferases; Protein; Trypanocidal; Trypanosoma; Trypanosomiasis; African; Uridine Diphosphate N-Acetylglucosamine

Diamond Keywords: Sleeping Sickness; Enzymes

Subject Areas: Chemistry, Biology and Bio-materials, Medicine

Instruments: I24-Microfocus Macromolecular Crystallography

Added On: 24/09/2015 13:06


Discipline Tags:

Infectious Diseases Health & Wellbeing Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech Parasitology

Technical Tags:

Diffraction Macromolecular Crystallography (MX)